Significant progress has been made in understanding the roles of FSH and LH on the growth and differentiation of the preovulatory follicle in primates. Information gained from these studies has rapidly been assimilated into new strategies for ovulation induction in clinical medicine. A major question that remains unsolved is the elucidation of the control mechanisms that govern the early stages of follicular development, as well as the mechanisms by which these early follicles become responsive to FSH. Because preovulatory follicles must come from the pool of early developing follicles, knowledge of the physiology of preantral and early antral follicles is essential to further the understanding and our ability to manipulate the ovarian cycle. Because of their important roles in early follicular development in rodents and the documented expression of these factors and their signal transduction pathways at comparable stages of folliculogenesis in primates, we have chosen to study the effects the oocyte product, GDF-9, and the granulosa cell product, activin, on early follicular development in macaque monkeys. We will use a novel drug delivery system to deliver GDF-9 and activin B directly to ovaries in vivo in combination with our previously developed "gonadotropin clamp" model, which allows us to isolate local ovarian actions of autocrine/paracrine agents from systemic effects of these agents on gonadotropin secretion. This unique system will thus permit us to determine the local ovarian effects of these factors independently of systemic effects that have confused the results from previous studies. The Specific Aims of this revised project are: Specific Aim 1. To prepare and characterize recombinant GDF-9 and activin B for in vivo studies in monkeys. Specific Aim 2. To determine the effects of recombinant activin B on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. Specific Aim 3. To determine the effects of recombinant GDF-9 on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. An understanding of the regulation and development of early follicles in primates will lead to the possibility of therapies aimed at enhancing a cohort of follicles several cycles away from ovulation. In particular, in women who are "poor responders" to our current ovulation induction therapies, a larger and healthier cohort of early antral follicles at the time of gonadotropin treatment would likely improve both the quantity and quality of mature preovulatory follicles. On the other hand, knowledge of the factors that govern early follicular growth would facilitate the development of novel methods of fertility control.